Vascular malformations of the brain account for roughly 10% of stroke syndromes. Clinically, an important subtype is brain arteriovenous malformation (BAVM). What is lacking in current research and the unifying theme of this proposal is a vertically integrated program that can relate clinical characteristics, notably risk of intracranial hemorrhage (ICH), with various aspects of the underlying genetic and cell-to cell signaling abnormalities. Project I (Young WL) will address BAVM clinical course in a cross-sectional and longitudinal cohort design to study various genotypes that can predict risk of spontaneous ICH. Project 2 (Hashimoto T) addresses cellular signaling in human surgical tissue specimens and relates patterns to Project I clinical variables determined. Project 3 (Boudreau N) examines the role of homeobox genes as master regulatory mechanisms in the regulation of extracellular matrix and angiogenesis. Project 4 (Nishimura S) investigates the role of astrocyte-endothelial cell interaction in a key signaling pathway for vascular homeostasis in the brain - integrin-mediated control of TGF-fl. The Data Management Core (McCulloch CE) organizes data input and analyses. The Laboratory Core (Yang GY) furnishes a murine model of brain angiogenesis for use in Projects 3 and 4, and some laboratory assays for Projects 1 and 4. The PPG is based on a three-pronged approach: first, the clinical behavior of the disease must be studied to identify natural tendencies likely to have biologic underpinning. These clinical behaviors can be associated with genotypic alterations. Second, biologic characteristics of diseased tissue need to be studied to confirm or rule out likely pathways relevant to the human disease. Such pathways need correlation to the clinical behavior of the disease to generate plausible hypotheses. Third, plausible hypotheses must be tested in animal models or cell culture systems to investigate and identify mechanistic components of relevance to the disease. Once such mechanistic components are identified, strategies to develop therapeutic approaches can be more rationally formulated. In such a triangulation of approaches, there is real promise for translational progress in the innovative therapy of brain vascular malformations.